Pathogenic bacteria responsible for infectious diseases were once thought to be controllable through the use of a battery of antibiotics such as penicillin, streptomycin, tetracycline, and others. However, since the widespread use of antibiotics began in the 1950s, more and more bacteria have evolved to become resistant to one or more antibiotics. Multiple drug-resistant strains are increasingly common, particularly in hospitals.
Currently, nosocomial Staphylococcal infections exhibit multiple drug resistance. See, for example, Archer et al., 1994, Antimicrob. Agents Chemother. 38:2231-2237. At this time, the remaining antibiotic that demonstrates the ability to kill most strains of Staphylococci is vancomycin. However, vancomycin resistant strains of both Staphylococcus and Enterococcus have already been isolated and reported by Zabransky et al., 1995, J. Clin. Microbiol 33(4):791-793. Furthermore, transfer of resistance from Enterococci to Staphylococci has been previously documented by Woodford et al., 1995, J Antimicrob. Chemother. 35:179-184. Streptococcus pneumoniae is a leading cause of morbidity and mortality in the United States (M. M. W. R., Feb. 16, 1996, Vol. 45, No. RR-1). Each year these bacteria cause 3,000 cases of meningitis, 50,000 cases of bacteremia, 500,000 cases of pneumonia, and 7,000,000 cases of otitis media. Case fatality rates are greater than 40% for bacteremia and greater than 55% for meningitis, despite antibiotic therapy. In the past, Streptococcus pneumoniae were uniformly susceptible to antibiotics; however, antibiotic resistant strains have emerged and are becoming widespread in some communities.
In addition, there are instances where antibiotic resistance is not an issue, yet a particular bacterium remains refractory to treatment using conventional antibiotics. Such is the case with Escherichia coli 0157:H7, a causative agent for food poisoning and death from undercooked meat. The Department of Agriculture estimates that 10 people die each day and another 14,000 become ill due to this bacterium. Unfortunately, conventional antibiotics are completely ineffective against this organism.
The history of antibiotic treatment of pathogenic bacteria is cyclical. Bacteria are remarkably adaptive organisms, and, for each new antibiotic that has been developed, resistant bacterial strains arise through the widespread use of the antibiotic. Thus, there is a constant need to produce new antibiotics to combat the next generation of antibiotic-resistant bacteria. Traditional methods of developing new antibiotics have slowed, and in the past two years, only one new antibiotic has been approved by the FDA. Furthermore, according to Kristinsson (Microb. Drug Resistance 1(2):121 (1995)), “there are no new antimicrobial classes with activity against resistant Gram positives on the horizon.”
There is a need for a compound that provides a compositional environment that will allow an increase in the efficacy of known antibacterial agents. There is also a need in the art for a compound that facilitates the activity of an active antibacterial agent, thus allowing the use of a lower amount or dose of antibiotic while reducing the development of resistant bacterial strains.
Viral disease is another health related disease state which threatens large segments of human populations. Some of the features related to viral infection which are of concern to health care professionals include its highly contagious nature (i.e., HIV, SARS etc) and high mutability. Some viruses are also oncogenic (such as HPV, EBV and HBV). While viruses are structurally amongst the simplest of organisms, they are regarded to be among the most difficult to control and present a formidable challenge for antiviral drug R&D.
Thus far, there have been a few antiviral drugs widely used in patients, such as Amantadine for flu, Acyclovir for HSV-related infections, Ganciclovir for CMV infection, and AZT, DDI and d4T for AIDS treatments. These drugs possess a variety of undesirable neurological, metabolic and immunological side-effects. Therefore, development of new antiviral therapy has become a major focus of medical and pharmaceutical research and development.
Nucleosides are natural metabolic products and precursors in human and animals. Modified nucleosides may have much lower toxicity to humans and thus have potential for use as safer antiviral drugs.